Cytokines are involved in many biological functions and are major mediators of the immune response. They are associated with the initiation and progression of various autoimnimune diseases. For example, tumor necrosis factor α (TNFα), interferon γ (IFNγ) and interleukin-1 (IL-1) have been associated with diabetes and the destruction of islet cells, the elevated production of Th2 cytokines have been associated with asthma, and interleukin-12 (IL-12) has been associated with rhuematoid arthritis.
Interleukin-9 (“IL-9” hereafter), is a glycoprotein which has been isolated from both murine and human cells. See, e.g., U.S. Pat. No. 5,208,218, incorporated by reference. This reference also teaches isolated nucleic acid molecules encoding the protein portion of the molecule, and how to express it.
Since its discovery as a T- and mast cell-growth factor produced by Th2 cells, the physiological processes in which for IL-9 is known to have a role have been gradually expanded (Uyttenhove, et al., Proc. Natl. Acad. Sci. USA 85:6934–6938 (1988); Hültner, et al., Eur. J. Immunol. 20:1413–1416 (1990); and Gessner, et al., Immunobiol. 189:419–435 (1993)) (Renauld, J.-C., & Van Snick, J. (1998), The Cytokine Handbook 313–331). Prominent features, disclosed by analysis of transgenic mice overexpressing IL-9, include increased susceptibility to lymphoma-genesis (Renauld, et al., Oncogene 9:1327–1332 (1994)), intestinal mastocytosis (Godfraind, et al., J. Immunol. 160:3989–3996 (1998)), expansion of the B-1 lymphocyte population (Godfraind, et al., J. Immunol. 160:3989–3996 (1998)), bronchial hyper-responsiveness (Temann, et al., J. Exp. Med. 188:1307–1320 (1998), and McLane, et al., Am J. Resp. Cell. Mol. 19:713–720 (1998)) and airway eosinophilia (Dong, et al., Eur. J. Immunol. 29:2130–2139 (1999)). In line with these observations, genetic analyses revealed a linkage between both IL-9 and IL-9 receptor (IL-9R) genes to human asthma (Holroyd, et al., Genomics 52:233–235 (1998) and Marsh, et al. Science 264:1152–1156 (1994)), a finding that was confirmed with respect to IL-9 in murine models (Nicolaides, et al., Proc. Natl. Acad. Sci. USA, 94: 13175–13180 (1997)).
Various uses of IL-9 are disclose in, e.g., U.S. Pat. No. 5,164,317 (proliferation of mast cells); U.S. Pat. Nos. 5,246,701 and 5,132,109 (enhancing production of IgG and inhibiting production of IgE), in addition to its first recognized utility, which is as a T cell growth factor. Exemplary of the vast scientific literature on IL-9 are Van Snick, et al, J. Exp. Med. 169(1): 363–368 (1989) (cDNA for the murine molecule, then referred to as P40). Houssiau, etal, J. Immunol 148, (10): 3147–3151(1992) (IL-2 dependence of IL-9 expression in T lymphocytes). Renauld, et al, Oncogene 9(5):1327–1332 (1994) (effect on thymic lymphomas); Renauld, et al, Blood 85(5):1300–1305 (1995) (anti-apoptotic factor for thymic lymphoma); U.S. Pat. No. 5,830,454 (treatments of cell mediated autoimmune disorders); and U.S. Pat. No. No. 5,935,929 (treating or preventing interstitial lung disease). Review articles may be found at, e.g., Renauld, et al, Cancer Invest, 11(5): 635–640 (1993); Renauld, et al, Adv. Immunol 54:79–97 (1993).
While detrimental in asthma, elevated production of Th2 cytokines has been reported to correlate with resistance to certain parasite infections (Finkelman, et al., Annu. Rev. Immunol., 15:505–533 (1997)). IL-9, for example, was found to enhance mouse resistance to infection with the caecal dwelling nematode T.muris (Faulkner, et al., Infect. Immun., 66:3832–3840(1998)). This resistance was associated with high IgE and IgG1 levels, as well as with pronounced intestinal mastocytosis.
The absence of T cell help has previously been suggested to be crucial for B cell tolerance toward self-proteins (Dalum, et al., J. Immunol., 157 ; 4786–4804 (1996)). Using bovine luteinizing hormone (LH) as a self protein coupled to ovalbumin (OVA), Johnson, et al. (J. Anim. Sci., 66, 719–726 (1988)) were able to induce high titers of autoantibodies against LH, causing cows to become anestrous. Similarly, a vaccine that prevents pregnancy in women was developed by coupling human chorionic gonadotropin and ovine luteinizing hormone to tetanus and diphtheria toxoids (Talwar, et al., Proc. Natl. Acad. Sci. USA, 91:8532–8536 (1994)). More recently, immunization with a fusion protein of an OVA epitope and mouse TNFα was found to prevent experimental cachexia and collagen-induced arthritis in mice (Dalum, et al., Nature Biotechnology, 17:666–669 (1999)).
Earlier attempts to generate autoantibodies capable of regulating biological processes, were successfully carried out mainly with hormones (Johnson, et al., J. Anim. Sci., 66:719–726 (1988) and Talwar, et al., Proc. Natl. Acad. Sci. USA, 91:8532–8536 (1994)), hormone receptors (Chackerian, et al. Proc. Natl. Acad. Sci. USA, 96:2773–2778 (1999)) or cellular components (Dong, et al., J. Exp. Med., 179:1243–1252 (1994) and Dalum, et al., Mol. Immunol., 34:1113–1120 (1997)). These observations were recently extended to cytokines with reports of anti-IFNα induction in AIDS patients (Zagury, et al., Biomed. Pharmacother, 53:90–92 (1999)) and of anti-TNFα vaccination in mice, the latter preventing cachexia and rheumatoid arthritis (Dalum, et al., Nature Biotechnology, 17:666–669 (1999)).